Gene therapy, though at its early development stage, holds promise for new treatments for various inherited and acquired skin diseases such as DNA-repair deficiency, differentiation disorder, skin cancer, wound healing, and hair loss. Other potential systemic applications by transection of skin cells such as immunization and production and secretion of gene products are evident. Foreign reporter and therapeutic genes have been directly introduced into skin cells using techniques such as gene gun, electroporation, punctuation and liposomes in vivo. However, the need for a safer, less invasive, more efficient and practical method of transection of a large area of skin cells still exists. We have recently designed and synthesized about seventy different cationic lipids in order to study the structure-activity relationship of this category of tranfection agents. Our initial screening process has revealed several novel cationic, micelle-forming lipids with excellent transection activity in mammalian cells in vitro. We hypothesize that by utilizing the latest developments from cationic lipid structure-activity studies, we can select the most potent lipid skin cell transection, and that DNA/lipid complex, in an appropriate formulation such as a hydrogel, can prolong the exposure time to the skin surface and thereby further increase transection efficiency. As an initial step towards developing an improved non-viral gene delivery system for skin diseases, we propose (1) to use a luciferase expression reporter plasmid to determine the transection efficacy of this series of improved lipids in karatinocytes and fibroblasts in vitro, and (2) to examine the effect of various types of DNA/lipids formulations on the efficacy of transdermal gene delivery in normal and wound skin models. The results for the proposed pilot study will help us to develop future gene therapy studies for skin diseases.